Venetoclax shows promise for ibrutinib-resistant CLL

The findings were consistent across a range of high-risk patient groups including those with baseline ibrutinib resistance mutations, for whom the allelic frequency of such mutations decreased with time on therapy.

Advertisement

This suggests that venetoclax has the potential “to eradicate ibrutinib-resistant clones” and “represents an important advance in the management of ibrutinib-resistant chronic lymphocytic leukaemia,” John Byrd (The Ohio State University, Columbus) and co-investigators remark.

The phase II multicenter trial included 91 patients with CLL whose disease progressed after ibrutinib therapy. They each received the orally bioavailable inhibitor of apoptosis regulator Bcl-2 venetoclax at a starting dose of 20 mg daily, increasing to 400 mg daily by week 5.

During a median follow-up period of 14 months, 65% of patients had an overall response. Among the responders, the median duration of response was not reached, and 88% were still responding at 12 months.

Three-quarters of patients were alive and progression-free at 12 months, with a median progression-free survival of 24.7 months. Median overall survival was not reached and 91% of participants were alive at 12 months.

Advertisement

The researchers note that high-risk patients with known del(17)(p13.1) or TP53 mutations (n=46) had a similar response to the full cohort, with an overall response of 61%, while the response was 71% among the 17 patients with BTK or PLCG2 mutations that are associated with ibrutinib resistance.

Furthermore, the allelic frequency of Cys481Ser BTK mutations decreased during up to 72 weeks of venetoclax treatment in eight patients with serial data available, but Byrd et al point out that the mutation tended to re-emerge before disease progression.

The team also reports that safety data were consistent with previous reports of venetoclax monotherapy in this group of patients.

Writing in The Lancet Oncology, Byrd and co-authors conclude: “Few effective options are available for patients with chronic lymphocytic leukaemia progressing on or after ibrutinib therapy; our data support the use of venetoclax monotherapy in this population.”

They add: “Further follow-up, with final analysis for this study planned for 2019, will help to better establish the durability of response to venetoclax in patients who have progressed on ibrutinib therapy.”

In an accompanying comment, Francesca Mauro and Robin Foà, both from Sapienza University in Rome, Italy, say the data show that venetoclax has the ability to overcome ibrutinib resistance.

“This new information is important for optimal management of patients with chronic lymphocytic leukaemia progressing on ibrutinib,” they write.

“Taken together, the results of this trial are reassuring and have relevant clinical implications, especially now that ibrutinib has been approved as a first-line treatment for patients with chronic lymphocytic leukaemia,” Mauro and Foà conclude.